Contribution To Literature:

The DAPT study showed that longer duration of DAPT following PCI results in lower stent thrombosis and recurrent MIs, but higher bleeding and all-cause mortality compared with a 12-month duration.

Description:

Current guidelines recommend that dual antiplatelet therapy (DAPT) with aspirin and an ADP receptor antagonist be continued for a minimum of 12 months following drug-eluting stent (DES) percutaneous coronary intervention (PCI). The optimal duration, however, remains unclear. This trial sought to investigate if 30 months of DAPT was superior to 12 months in patients undergoing DES and bare-metal stent (BMS) PCI.

Study Design

Placebo-controlled

Randomized

Blinded

Parallel

Patient Populations:

Age >18 years

PCI with stent deployment within the past 24 hours

No known contraindication to DAPT for at least 30 months after enrollment and stent implantation

Secondary Endpoints:

All-cause mortality

Drug/Procedures Used:

Patients were enrolled 72 hours after stent placement and were given open-label aspirin and thienopyridine for 12 months, per current practice norms. At 12 months, patients without an ischemic or bleeding complication and with documented compliance, were randomized in a 1:1 fashion to receive an additional 18 months of DAPT or matching placebo. Stratification was performed based on DES versus bare-metal stents (BMS), hospital, clopidogrel versus prasugrel, and risk factors for stent thrombosis.

Principal Findings:

DES PCI: A total of 9,961 patients were randomized at 452 sites in 11 countries: 5,020 to prolonged DAPT and 4,941 to placebo. Baseline characteristics were fairly similar between the two arms. Approximately 30% had diabetes mellitus, 25% were smokers and 6% had peripheral arterial disease. Indication for PCI was stable angina in 38%, ST-segment elevation myocardial infarction (STEMI) in 10% and NSTE-acute coronary syndrome (NSTE-ACS) in 32%. Approximately two thirds of the patients received clopidogrel, whereas the rest received prasugrel. Stents implanted during index PCI was everolimus-eluting stent (EES) in 47%, paclitaxel-eluting stent (PES) in 27%, zotarolimus-eluting stent (ZES) in 13%, sirolimus-eluting stent (SES) in 11%, and multiple in the others. The mean number of lesions treated was 1.1, with about 1.5 stents/patient. The vessel treated was left anterior descending in 41% and right coronary artery in 32%.

MI risk: Discontinuing thienopyridine after either 12 or 30 months was associated with an early increase in MI risk. The majority of MIs (~75%) occurring after thienopyridine discontinuation were not related to stent thrombosis. MI risk was noted in patients with both low and high DAPT scores.

Interpretation:

The results of the DAPT trial indicate that prolonged duration of DAPT up to 30 months following index PCI with a DES results in lower stent thrombosis and recurrent MIs compared with a 12-month duration of DAPT, although bleeding and all-cause mortality were higher with prolonged therapy. The BMS subset shows a less impressive treatment effect, although the p-value for interaction between DES versus BMS was not significant. Similarly, the EES subset showed no difference for the primary endpoint with prolonged therapy. Both stent thrombosis and spontaneous MIs were reduced in DES patients, but not in BMS patients. The mechanism of benefit is unclear, since a non-stent thrombosis-related MI reduction would be expected to be observed equally in DES and BMS patients. In the propensity-matched analysis, the highest difference between DES and BMS for stent thrombosis and MACCE appeared to be within the first year (while on open-label DAPT). The DAPT score may be a useful tool for individualizing decisions regarding dual antiplatelet duration in patients post-PCI, but will need further validation.

Following concerns regarding late and very late stent thrombosis with first-generation DES, American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommended a minimum duration of 12 months of DAPT following DES PCI. However, the optimal duration remains unknown and trials have sought to study both sides of the duration spectrum. On the one hand, trials such as PRODIGY, RESET, and OPTIMIZE sought to assess shorter durations (3-6 months) of DAPT with at least 50% second-generation DES use in mostly stable patients. On the other hand, trials such as DES-LATE and EXCELLENT sought to assess if prolonged DAPT treatment would be superior to 12 months.

The DAPT trial is the largest trial on this topic to date, and suggests that although there may be an ischemic benefit with prolonged DAPT therapy, there is a price to pay in terms of bleeding risk. The excess in mortality is concerning, and appears to be predominantly due to cancer-related mortality. It is unclear if this is a chance finding or a true biological effect. Moreover, these results only apply to patients who have not had an ischemic or bleeding event within the first year, and were also fully compliant with DAPT therapy, thus somewhat limiting the generalizability of this trial. Patients in this trial received contemporary stents, although nearly a quarter received PES, which are inferior to EES and ZES. The magnitude of benefit appeared to be highest in the PES patients, and lower in patients receiving EES. It is unclear to what extent this trial will immediately impact clinical practice. Further follow-up and data from other ongoing trials are awaited.